Maze Therapeutics’ MZE782 Shows Strong Phase 1 Data, Targets PKU and CKD

Maze Therapeutics has announced encouraging first-in-human Phase 1 results for MZE782, its lead SLC6A19 inhibitor, setting the stage for potential first-in-class development in chronic kidney disease (CKD) and best-in-class competition in phenylketonuria (PKU).

Phase 1 Data Exceed Expectations
In healthy volunteers, MZE782 demonstrated robust pharmacodynamic effects:

• A 39-fold increase in urinary phenylalanine excretion at a single 960 mg dose.
• A 42-fold increase at 240 mg twice-daily dosing.

These results exceeded Maze’s prior internal expectations (>10-fold in PKU, >15-fold in CKD), underscoring the compound’s differentiation. Importantly, an early, dose-dependent dip in eGFR was observed, reminiscent of SGLT2 and RAAS inhibitors, suggesting possible kidney-protective effects—a feature that could support its CKD label expansion.

Maze plans to advance MZE782 into Phase 2 studies in 2026 with plasma phenylalanine reduction as the key endpoint in PKU and proteinuria reduction in CKD, a surrogate endpoint that may enable accelerated approval pathways.

Competitive Landscape in PKU

The PKU field has become increasingly crowded with diverse approaches:

• Sepiapterin (PTC Therapeutics, brand name Sephience):
  Approved in the US (July 2025) and EU (June 2025) for hyperphenylalaninemia in PKU. Sepiapterin is a phenylalanine hydroxylase activator, distinct mechanistically from transporter inhibitors.
• JNT-517 (Jnana Therapeutics / Otsuka):
  An oral SLC6A19 inhibitor in Phase 2, supported by strong reductions in plasma phenylalanine in early trials. In 2024, Otsuka licensed the asset for up to $800 million, highlighting big pharma’s confidence in the modality. Marketed as the first-in-class oral approach for PKU, though not yet approved.
• Pegvaliase (BioMarin, Palynziq):
  An enzyme substitution therapy already on the market, though limited by tolerability and complex administration.
• Other Emerging Approaches:
  Gene therapy (BioMarin’s BMN-307, though paused due to safety concerns), mRNA-based therapies, and next-generation oral modulators are also in development.

Against this backdrop, Maze is positioning MZE782 as best-in-class in PKU—with stronger biomarker effects than JNT-517—and first-in-class in CKD, where no other SLC6A19 inhibitors are in the clinic.

Strategic Implications

Maze’s data raise the competitive stakes in PKU drug development:

• If replicated in patients, MZE782’s >40x urinary phenylalanine excretion effect could materially outpace Jnana/Otsuka’s JNT-517.
• The dual PKU + CKD strategy differentiates Maze from other players, providing a broader commercial runway.
• With PTC’s Sepiapterin now approved, and BioMarin’s enzyme therapies established, the entry of transporter inhibitors could re-shape the treatment paradigm toward oral, mechanism-diverse options.

Outlook

Maze expects to launch Phase 2 trials in 2026, with potential regulatory tailwinds if proteinuria reduction in CKD is confirmed. With multiple validated mechanisms now converging on PKU, the next five years will likely define whether SLC6A19 inhibition can displace or complement existing standards of care.

Sources

• Maze Therapeutics. Positive First-in-Human Results for MZE782, a Potential First-in-Class Therapy for CKD and Best-in-Class for PKU. Sept 2025.
• Jnana Therapeutics. JNT-517 Positive Clinical Proof of Concept in PKU. 2025.
• PTC Therapeutics. Sepiapterin Approved in EU and US for Hyperphenylalaninemia due to PKU. 2025.
• FierceBiotech. Otsuka Pays $800M to Jnana for PKU Drug JNT-517. Apr 2025.
• DelveInsight. PKU Clinical Pipeline Report. Apr 2025.